96 research outputs found
Measuring socio-demographic differences in volunteers with a value-based index: illustration in a mega event
The phenomenon of volunteering can be analysed as a consumer experience through the concept of value as a trade-off between benefits and costs. In event volunteering, both the expected value (pre-experienced) and the perceived value (post-experienced) of volunteering can be assessed. With this purpose, an online quantitative survey is conducted with a sample of 711 volunteers in a religious mega event, with questions related to five dimensions of their experience: efficiency, social value, play, spirituality and time spent. These five scales, properly tested are used for building a multidimensional index of both the expected and perceived value of the volunteer experience. ANOVAs test show significant differences on the index in both moments upon the socio-demographic profiles: negative expectations/experience balance by age, contrasted results by sex, and more experienced volunteers being more critical with the value experienced. Implications for event managers are proposed, in line with the motivation of volunteers
p21-activated kinase signaling in breast cancer
The p21-activated kinases signal through a number of cellular pathways fundamental to growth, differentiation and apoptosis. A wealth of information has accumulated at an impressive pace in the recent past, both with regard to previously identified targets for p21-activated kinases that regulate the actin cytoskeleton and cellular stress pathways and with regard to newly identified targets and their role in cancer. Emerging data also provide new clues towards a previously unappreciated link between these various cellular processes. The present review attempts to provide a quick tutorial to the reader about the evolving significance of p21-activated kinases and small GTPases in breast cancer, using information from mouse models, tissue culture studies, and human materials
PAK4 signaling in development and cancer
Our understanding of cancer biology has been evolving rapidly shaped by groundbreaking
discoveries. We now understand that cancer is not one disease but many, and that tumors are
not foreign objects in the human body but rather the result of changes in the previously normal
tissues and organs. Thus, in order to ask fundamental questions and dissect the complexity of
cancer it is essential to grasp how the healthy organs develop and function and the cellular and
molecular mechanisms involved. The serine/threonine PAKs are signaling hubs with proven
roles in development and disease. Specifically, they are important to several hallmarks of
cancer. Thus, the family in general, and PAK4 in particular, is increasingly attracting the
interest of the scientific community.
In this thesis I have explored the role of PAK4 in normal organ development and cancer. Novel
mouse models with PAK4 depletion in the mammary gland and in the pancreas have been
established and characterized in Paper I and Paper II. The absence of major tissue
abnormalities upon PAK4 depletion in the mammary epithelium allowed me to use this model
to study the role of PAK4 in tumorigenesis in vivo, in Paper III, and a counterpart mouse
model with PAK4 overexpression in the mammary epithelium was also generated. These
complementary in vivo setups showed that PAK4-overexpressing mammary glands
occasionally developed mammary tumors while PAK4 abrogation impaired PyMT-driven
mammary tumorigenesis. Extensive in vitro experiments, using state of the art techniques, then
supported a model in which PAK4 confers selective advantages to cancer cells by overcoming
the senescence barrier. This, in turn, constitutes a selective vulnerability of cancer cells that
become susceptible to a senescence-like response upon PAK4 inhibition. The data presented
also demonstrates a crosstalk between PAK4 and NF-κB signaling, and a direct interaction and
phosphorylation site within the REL-homology domain of RELB is found to be relevant for
tuning RELB-mediated transcription and cancer cell proliferation via C/EBPβ. Importantly,
these findings were largely supported by correlations in clinical data and validated ex vivo in
patient-derived cells, thus highlighting PAK4 as an attractive therapeutic opportunity in cancer.
Therefore, this thesis contributes to a better understanding of the mechanisms that govern breast
tumorigenesis, with hopes that such knowledge will prove relevant in cancer prognosis and
treatment
PAK4 kinase activity and somatic mutation promote carcinoma cell motility and influence inhibitor sensitivity
Hepatocyte growth factor (HGF) and its receptor (c-Met) are associated with cancer cell motility and invasiveness. p21-activated kinase 4 (PAK4), a potential therapeutic target, is recruited to and activated by c-Met. In response, PAK4 phosphorylates LIM kinase 1 (LIMK1) in an HGF-dependent manner in metastatic prostate carcinoma cells. PAK4 overexpression is known to induce increased cell migration speed but the requirement for kinase activity has not been established. We have used a panel of PAK4 truncations and mutations in a combination of over-expression and RNAi rescue experiments to determine the requirement for PAK4 kinase activity during carcinoma cell motility downstream of HGF. We find that neither the kinase domain alone nor a PAK4 mutant unable to bind Cdc42 is able to fully rescue cell motility in a PAK4-deficient background. Nevertheless, we find that PAK4 kinase activity and associated LIMK1 activity are essential for carcinoma cell motility, highlighting PAK4 as a potential anti-metastatic therapeutic target. We also show here that overexpression of PAK4 harboring a somatic mutation, E329K, increased the HGF-driven motility of metastatic prostate carcinoma cells. E329 lies within the G-loop region of the kinase. Our data suggest E329K mutation leads to a modest increase in kinase activity conferring resistance to competitive ATP inhibitors in addition to promoting cell migration. The existence of such a mutation may have implications for the development of PAK4-specific competitive ATP inhibitors should PAK4 be further explored for clinical inhibition
Ubiquitin Ligase HUWE1 Regulates Axon Branching through the Wnt/beta-Catenin Pathway in a Drosophila Model for Intellectual Disability
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126190.pdf (publisher's version ) (Open Access)We recently reported that duplication of the E3 ubiquitin ligase HUWE1 results in intellectual disability (ID) in male patients. However, the underlying molecular mechanism remains unknown. We used Drosophila melanogaster as a model to investigate the effect of increased HUWE1 levels on the developing nervous system. Similar to the observed levels in patients we overexpressed the HUWE1 mRNA about 2-fold in the fly. The development of the mushroom body and neuromuscular junctions were not altered, and basal neurotransmission was unaffected. These data are in agreement with normal learning and memory in the courtship conditioning paradigm. However, a disturbed branching phenotype at the axon terminals of the dorsal cluster neurons (DCN) was detected. Interestingly, overexpression of HUWE1 was found to decrease the protein levels of dishevelled (dsh) by 50%. As dsh as well as Fz2 mutant flies showed the same disturbed DCN branching phenotype, and the constitutive active homolog of beta-catenin, armadillo, could partially rescue this phenotype, our data strongly suggest that increased dosage of HUWE1 compromises the Wnt/beta-catenin pathway possibly by enhancing the degradation of dsh
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